No one needs to be told about the opioid painkiller problem in this country. There are legal, commerical, regulatory, and ethical ways to look at it, but from a pharmacological standpoint, the whole thing would be a lot easier to deal with if there were any highly effective non-addictive painkillers. But that’s exactly what we lack. Pain, as a therapeutic area, has been very painful indeed over the years, with a lot of good ideas that have wiped out in actual clinical trials. There are actually several different kinds of pain signals that differ in both degree and kind, and we still have not untangled what’s going on with all of them.
You could imagine two general approaches to the problem. Searching for new pain mechanisms is the one that most people have been trying, in the hopes that these will not have the addiction potential that the opioid receptors do, but that’s what’s led to all sorts of ion-channel (and other receptor) failures. Another way to approach the problem would be to find a way to hit those opioid receptors without causing addiction, but that’s not easy to picture. Last year, though, there was a report of a compound (an orvinol derivative) that simultaneously hits mu-opioid receptors and nociceptin receptors, and in primate models it showed analgesia but not addictive potential, which is definitely interesting.
This new paper in Science takes another ingenious approach (here’s a story on it at Ars Technica). The authors, a team from Berlin, noted that inflamed and injured tissues generally have lower (more acidic) pH than normal. They hypothesized that the mu-opioid receptor itself might have different behavior under those conditions, which might be exploited by a compound that would be less active in normal tissues. A fluorinated derivative of fentanyl seemed to meet those conditions in cell assays, showing pH-sensitive activity. When dosed in rodents, it seems to have a very different profile from fentanyl itself, showing pain relief only at the site of injury. A non-centrally-acting opioid antagonist can only partially reverse the effects of fentanyl, since some of those are from inside the CNS, but the same agonist seems to completely reverse the effects of the fluorinated compound. And it also shows no addiction potential, GI or respiratory effects, or sedation, all of which are hallmarks of classic opioid agonists. (The compound from the 2016 paper mentioned above was also devoid of these effects).
These sorts of results are very hopeful, and I hope that such compounds advance to human trials as soon as possible. Pain is an awful problem, but by treating it with addictive compounds medicine has added another hideous problem on top of it. If we can get to the point of being able to regard classical opioid drugs as barbaric remnants of an earlier age, that would be a great improvement.
Update: be sure to have a look at the comments. There are some good arguments for why these approaches may not translate, so this will be worth watching to see how they progress.